Mutant NPM1-regulated estrogen signaling promotes leukemia cell survival by upregulating HGF and represents a therapeutic vulnerability.

Acute myeloid leukemia (AML) with mutated nucleophosmin 1 (NPM1) presents therapeutic challenge and exhibits a striking female predominance in clinical. However, the contribution of gender-specific factors, such as sex hormones to the pathogenesis and therapeutic implications in NPM1-mutated AML remains elusive. In the present study, we found that NPM1-mutated AML showed female bias, particularly among the young, pre-menopausal age (20-49 years) group, and that female exhibited inferior overall survival compared to males. Subsequently, 17β-estradiol (E2), the primary circulating estrogen in pre-menopausal females, was shown to facilitate the proliferation of NPM1-mutated leukemia cells. Importantly, ovariectomy (OVX) alleviated the leukemia burden, while reintroduction of exogenous E2 accelerated disease progression in leukemia mouse models. Mechanistically, leukemia cells exhibited an estrogen receptor α (ERα)-dominant/ERβ-low expression signature, which was maintained through NPM1 mutant-induced ubiquitination-dependent degradation of ERβ. The diminished ERβ level allowed ERα to act as the primary responder of E2, evidenced by the nuclear translocation of ERα following E2 treatment. Transcriptomic analysis identified hepatocyte growth factor (HGF) as the potential target of E2 signaling, and E2-mediated ERα activation transcriptionally upregulated HGF, thus promoting leukemia cell proliferation. Therapeutically, blockade of the E2/ER pathway using selective ER degrader fulvestrant inhibited the growth of NPM1-mutated AML cells, and its combination with chemotherapy drug cytarabine induced synergistic anti-leukemia effects in vitro and in vivo. Collectively, these data demonstrated the oncogenic role of E2/ERα signaling in NPM1-mutated leukemia and suggested that targeting E2/ERα signaling combined with standard chemotherapy may represent a promising regimen for female patients.